Is LITAF p.Ser2Leu (c.5C>T) pathogenic?

LITAF p.Ser2Leu (c.5C>T) is classified Uncertain significance in LITAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.2532); Very rare (popmax 0.00223%, eas); Associated with Charcot-Marie-Tooth disease type 1C.

What condition is associated with LITAF p.Ser2Leu (c.5C>T)?

LITAF p.Ser2Leu (c.5C>T) is associated with Charcot-Marie-Tooth disease type 1C (ClinVar).

How common is LITAF p.Ser2Leu (c.5C>T) in the general population?

LITAF p.Ser2Leu (c.5C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Charcot-Marie-Tooth disease type 1C inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LITAF p.Ser2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2532) — an in-silico prediction, not a clinical call.

LITAF p.Ser2Leu

c.5C>T · rs760802727 · VCV2141094

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Charcot-Marie-Tooth disease type 1C

Computational evidence

Protein change
AlphaMissense	0.2532	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.6	GERP 0.85, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,090 bp · p 0.61 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,896 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000682% 11/1,613,616 alleles · very rare exomes 10/1,461,496 · genomes 1/152,120 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
South Asian	0.0022%	45,516
Admixed American	0.00167%	59,986
European (non-Finnish)	0.000593%	168,534

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LITAF
Protein: p.Ser2Leu
Coding: c.5C>T
MANE Select: NM_001136472
dbSNP: rs760802727
Type: single nucleotide variant
Location: chr16:11556726 (GRCh38)
Gene constraint: LOEUF 1.017 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 70.60
Residue 2: the 'disordered' region

Full LITAF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease type 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Charcot-Marie-Tooth disease type 1C (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

LITAF p.Ser2= Benign/Likely benign ★★ same residue
LITAF p.Ala111Gly Pathogenic ★★ same condition
LITAF p.Gly112Ser Pathogenic ★★ ⚠ same condition
LITAF p.Thr115Asn Pathogenic/Likely pathogenic ★★ same condition
LITAF c.220+4C>T Uncertain significance ★★ same condition
LITAF p.Ala129Val Uncertain significance ★★ ⚠ same condition
LITAF p.Ala140Thr Uncertain significance ★★ ⚠ same condition
LITAF p.Ala153Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/litaf-p-ser2leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown